In mice, there are more than 30 different retinal ganglion cell types that encode the visual scene, transmitting information about motion direction, orientation, location, size and luminance. These cell types provide rich detail about the surrounding environment. However, during certain brain states and behaviors, some channels of information are more important than others. For example, during locomotion or foraging, visual processing of objects in front of you may be more important than detection of certain visual cues, such as weak threat cues from looming predators. Recent studies in the cortex and thalamus have identified synaptic and circuit mechanisms that heighten sensitivity to specific relevant visual stimuli and/or suppress irrelevant information depending on brain state. In this proposal, the Chen and Andermann laboratories propose to test a hypothesis that state-dependent modulation of visual sensitivity begins at a much earlier station in the visual pathway, at the level of the retinal ganglion cell terminals as they innervate the dorsal lateral nucleus (LGN), the visual thalamus. Further, this sensitivity may be conferred by direct neuromodulatory actions of serotonin. The Andermann lab will image visual responses from retinal axonal boutons of different retinal ganglion cell types across states of quiet waking and arousal while manipulating serotonergic signaling in LGN. The Chen lab will perform in vitro electrophysiology experiments to assess the magnitude of presynaptic modulation by serotonin in distinct genetic classes of retinal inputs to LGN, using two-color optogenetic activation of genetic subtypes of retinal axons, together with stimulation of serotonergic axon terminals in LGN. If our hypotheses are confirmed, this synergistic collaboration between the two labs will establish a conceptually novel framework for understanding behavioral modulation of early visual processing and perception, and provide important insights into disorders of cognition and visual perception.